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HEMOGLOBINOPATHY

A combination of two novel alpha globin variants Hb Bridlington (HBA1) and Hb Taybe (HBA2) resulting in severe hemolysis, pulmonary hypertension, and death

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Abstract

Objective and importance

To describe two novel hemoglobin mutations that resulted in an unstable hemoglobin with a severe hemolytic phenotype.

Clinical presentation

A patient with an unstable hemoglobin and chronic hemolysis underwent splenectomy at age 15, subsequently developing chronic thrombo-embolic pulmonary hypertension at age 27 that was ultimately fatal.

Intervention

DNA sequencing of the alpha globin gene revealed heterozygous inheritance of Hb Taybe, arising from a novel mutation in the HBA2 gene and Hb Bridlington, a novel HBA1 mutation. Greater disease severity is predicted by the position of the Hb Taybe mutation on the HBA2 gene (which transcribes more globin than the HBA1 gene).

Conclusion

Splenectomy was not clearly beneficial and may have contributed to the development of pulmonary hypertension. The case favors a cautious approach when considering splenectomy for patients with Hb Taybe.

Introduction

Unstable hemoglobin disorders are an inherited cause of hemolytic anemia. Mutations result in an unstable hemoglobin tetramer which precipitates intracellularly, reducing red cell survival and causing chronic hemolysis of variable severity. Hemolysis may worsen with intercurrent infection or treatment with oxidant drugs. Although therapeutic splenectomy has been used in hemolytic conditions, there appears to be an increased risk of vascular complications including pulmonary hypertension.Citation1

Hemoglobin (Hb) Taybe is a highly unstable alpha globin variant which results from a 3 bp deletion at codon 38 or 39 of the HBA1 gene. Hb Taybe caused by a mutation in the HBA2 gene has not been previously described. Here we report a patient heterozygous for Hb Taybe resulting from a novel mutation in the HBA2 gene (HBA2:c.118_120delACC)Citation2 and a second novel alpha globin variant (HBA1:c.98T > C) which was named Hemoglobin Bridlington.Citation2 The combination of these trans inherited mutations gave rise to hemolytic anemia. The patient underwent splenectomy at age 15 and developed thrombo-embolic pulmonary hypertension in her mid-20s.

Case report

A 30-year-old Caucasian woman was referred for ongoing support of congenital hemolytic anemia. She first presented in childhood with jaundice and abdominal pain. She was found to have splenomegaly, gall stones, and hemolytic anemia. At the age of 11, genotyping revealed a novel mutation at codon 32 of the alpha 1 globin gene (Met → Thr). Her mother tested negative for this. It was concluded that this had caused an unstable hemoglobin, resulting in hemolysis. She went on to have splenectomy and cholecystectomy at age 15. Pre-operative hemoglobin was 101 g/l and bilirubin 65 µmol/l. She was subsequently lost to follow-up.

She re-presented at age 27 with a 3-year history of exertional dyspnea progressing to breathlessness on minimal exertion and bilateral pleuritic chest pains. Computed tomographic pulmonary angiography demonstrated multiple pulmonary emboli. Echocardiogram documented a dilated right heart, impaired right ventricular function, and tricuspid regurgitation with an estimated pulmonary artery pressure of 56 mmHg plus right atrial pressure. Thrombophilia screening was negative except for low protein C and S due to warfarin anticoagulation. Chronic thrombo-embolic pulmonary hypertension was subsequently confirmed on right heart catheter studies, but she was unsuitable for pulmonary thromboendarterectomy due to distal disease. Initial treatment was with warfarin, long-term oxygen therapy (mean overnight oxygen saturations 89% on room air), and sildenafil.

She was assessed by adult hematology services at age 30. She was British Caucasian but recalled that her mother's father was said to have ‘funny Spanish blood’. Her exercise tolerance was 1–2 miles and medications were penicillin V, lansoprazole, sildenafil, and warfarin. Examination revealed a splenectomy scar but no cyanosis or jaundice. Investigations were consistent with hemolysis: LDH 1017 IU/l (NR 160–430), bilirubin 58 µmol/l (NR 5–21), haptoglobin <0.06 g/l (NR 0.4–1.6), hemoglobin 109 g/l, mean cell volume 91 fl (NR 78–100), reticulocyte count 367 × 109/l (NR 20–80). Blood film showed nucleated red cells, Howell Jolly bodies, spherocytes, and occasional basophilic stippling. Serum B12, folate, and ferritin were normal. In the light of childhood investigations, DNA sequencing of the alpha and beta globin genes was carried out, and a family study was subsequently conducted (). The novel mutation (HBA1:c.98T > C) was confirmed and named Hb Bridlington, but additionally, the alpha mutation Hb Taybe (HBA2:c.118_120delACC) was identified and the severity of the hemolysis was attributed to the combination. The novel mutation could also be detected by tandem mass spectrophotometry. This revealed a −30 Da mass change at b2 and the occurrence of no mass change in all the y ions up to and including y8 showing the mutation to be α32 Met to Thr.

Table 1. Hematological indices and alpha globin genotypes for the proband and four family members

Unfortunately, the patient's breathing deteriorated. Although she responded to intravenous iloprost and diuretics, she died from progressive right heart failure due to chronic thrombo-embolic pulmonary hypertension (CTEPH) 3 years later, despite the use of combination pulmonary vasodilator therapy.

Discussion

The novel alpha hemoglobin variant Hb Bridlington was detected by the original investigations in 1991. It does not separate from Hb A on high-performance liquid chromatography (HPLC) or electrophoresis but is detectable by mass spectrophotometry. The co-existing presence of Hb Taybe was not identified in the original analysis, most likely because it is hyper-unstable and therefore only very small quantities will be present in the peripheral blood. These low levels are unlikely to be detected by conventional protein based methodologies such as HPLC, electrophoresis or even mass spectrophotometry. Hb Taybe carriers have a benign α+-thalassemia phenotype but when homozygous or doubly heterozygous with other alpha globin gene mutations, Taybe can result in moderate to severe hemolytic anemia.Citation3Citation6 Hb Taybe has previously been described in individuals of Israeli-Arab, Greek, and Italian descent.Citation7 All cases of Taybe in the literature report the mutation to be in the HBA1 gene; therefore, it is a novel finding that this patient has the mutation in the HBA2 gene. This is significant as the HBA2 gene transcribes twice as much globin as the HBA1 gene. Therefore mutations in the HBA2 gene usually produce a more severe phenotype than those in the HBA1 gene.Citation8 The novel α1 variant Hb Bridlington is predicted to be mildly unstable due to its proximity to the α1β1 contact site. The patient's father was heterozygous for Hb Bridlington and had mild anemia and slight reticulocytosis (), but these parameters may have been adversely affected by co-morbidity (rheumatoid arthritis). The patient's mother and sister were both found to be carriers of Taybe (HBA2). The sister was clinically asymptomatic but had slight hypochromia and an increased reticulocyte count (153 × 109/l) consistent with mild hemolysis. The mother was also clinically asymptomatic with an increased reticulocyte count (119 × 109/l); however, her red cell indices were normochromic (). Therefore like HBA1 Taybe carriers, HBA2 Taybe carriers appear to have a mild phenotype with minimal hematological abnormalities. The finding of reticulocytosis suggesting mild hemolysis in both mother and daughter could however hint at a slightly more severe phenotype than has been observed in HBA1 Taybe carriers, where the reticulocyte levels have been mostly reported as normal.Citation3,Citation6 The severity of hemolysis in the patient was most likely due to the co-inheritance of the highly unstable Hb Taybe (possibly exacerbated by the occurrence of the mutation on the HBA2 gene) and the mildly unstable Hb Bridlington.

Hemolytic anemia is a recognized cause of pulmonary hypertensionCitation9 and is likely to have been the underlying cause in this young woman who had no other risk factors such as pre-existing autoimmune, respiratory or cardiac disease. Therapeutic splenectomy may be carried out in a number of hereditary hemolytic conditions such as hereditary spherocytosis and thalassemia. However, splenectomy is also thought to be a risk factor for vascular complications, including small vessel CTEPH disease and that risk appears greatest in patients with ongoing hemolysis.Citation1 In an international registry reporting on 679 patients with CTEPH, 3.4% had undergone prior splenectomy, and splenectomy was associated with non-operability.Citation10 Interestingly, another patient compound heterozygous for Hb Taybe and a HBA2 gene mutation (IVS-I donor site 5 bp deletion) underwent splenectomy at age 19 for fatigue and icterus without significant improvement of Hb or hemolysis. The patient developed thrombotic events 5 years later with priapism, followed by a pontine infarction at age 28. In that case, a heterozygous mutation for PT20210 was also noted.Citation11

We report two novel unstable hemoglobin variants, Hb Bridlington and Hb Taybe, on the HBA2 gene, presenting together in trans. Both hemoglobin variants are not easily detectable by conventional protein based methodology (HPLC or electrophoresis) indicating the importance of DNA studies in such cases. The hemolytic anemia resulting from the combination was treated with splenectomy and led to pulmonary hypertension. Neither this nor the recent case described above had a significant response to splenectomy and serious vascular complications developed in both. These reports favor a cautious approach when considering splenectomy for patients with Hb Taybe.

Disclaimer statements

Contributors QAH was involved in the care of the patient and wrote the manuscript; LF was involved in the diagnosis, and reviewed and approved the final manuscript; JL was involved in the care of the patient, and reviewed and approved the final manuscript; AG was involved in the diagnosis, and reviewed and approved the final manuscript; SH was involved in the diagnosis of the patient and wrote the manuscript.

Funding None.

Conflicts of interest None.

Ethics approval This was an observational retrospective case report and no ethical approval was not required.

Acknowledgements

Thanks to Brian Green, who reported the novel mutation Hb Bridlington on tandem mass spectrophotometry, for discussions on the reporting of this technique.

References

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